JP2004532656A - In situ bioartificial filler and method for in situ formation of bioartificial discs - Google Patents

Abstract

Bioprosthetic devices include an exterior biological tissue member which at least partly defines a cavity, and a proteinaceous biopolymer which fills the cavity, and intercalates and is chemically bound (fixed) to the tissue of the surrounding biological tissue member. In preferred forms, the bioprosthetic device is a bioprosthetic vertebral disc having a fibrillar outer annulus which surrounds and defines an interior cavity and is formed by removal of at least a substantial portion of the natural gelatinous core therefrom. The cavity defined by the fibrillar outer annulus may then be filled with a flowable proteinaceous biopolymer. Preferably, the proteinaceous biopolymer is a liquid mixture comprised of human or animal-derived protein material and a di- or polyaldehyde, which are allowed to react in situ to form a cross-linked biopolymer within the cavity. The liquid mixture may be formed in advance of being introduced into the cavity, or may be formed simultaneously during introduction into the cavity.

Description

[0001]
(Cross reference of related application)
This application is based on co-pending US Provisional Application No. 60 / 242,457, filed Oct. 24, 2000, which gives the benefit of the national priority under 35 USC 110 (e). And all of its contents are incorporated herein by reference.
[0002]
TECHNICAL FIELD OF THE INVENTION
The present invention relates generally to bioprostheses, and in particular, in a preferred embodiment, the invention relates to bioprostheses formed in situ.
[0003]
[Prior art]
The disc is a collagenous spacer located between the vertebrae of the spine. The disc is generally composed of a rigid fibrous outer ring (annulus fibrosus) and a hyperhydrated glue-like core (nucleus pulposus). The intervertebral disc functions as a shock absorber, dissipating the energy of impacts on the back as well as the joints, allowing the human torso to flex and stretch.
[0004]
Disc deformation in the lumbar portion of the spine is a major cause of debilitating low back pain in adults over 35 years of age. Intervertebral disc deformity (DDD) is characterized by a gradual collapse of the disc due to dehydration of the nucleus pulposus or due to bulging of the annulus fibrosus. DDD accelerates the formation of fissures in the annulus, protrudes the nucleus of the disc (disc herniation), and may lead to sudden contraction of the disc height and possible nerve root and / or spinal compression. Herniated discs can also result from trauma associated with spinal load compression, such as sitting down and falling sharply.
[0005]
Chronic diffuse low back pain results from stimulation of pain receptors in the outer third disc annulus and surrounding soft tissue upon disc collapse. Root pain results from direct compression of nerve roots affected by protruding or swollen disc tissue. Intense and extensive physical and drug treatments are at the forefront of debilitating back pain. Failure to resolve acceptable pain indicates surgical intervention.
[0006]
Traditional surgical procedures for the treatment of intractable back pain with DDD include fusion of the bodies of the vertebrae above and below the affected disc, or incision, microsurgical, or endoscopic methods. Requires removal of nuclear material through Recently, new methods have been applied that involve heat shrinkage of the glue plate with an electrothermal catheter or laser device. Removal of the nucleus leaves a void inside the disc, eliminating viscoelastic fluids that act as shock absorbers. This void and viscoelastic fluid creates an opportunity for the disc to collapse internally, allowing the disc space to collapse further. Disintegration of the disc space can result in loss of motility and morbidity as nerves emanating from the spine are clamped during the collapse of the disc space.
[0007]
Many surgical techniques and specialized equipment have been created to combat the problem of progressive disc collapse resulting from nuclear ejection of the disc. The collected autologous bone is located inside the nucleated disc space and bridges or fuses the bone between the two vertebral bodies. Stem screws and other spinal tools, such as rods and plates, mechanically secure the vertebral body, stabilize the vertebrae and prevent further collapse. The problem with these and other fusion techniques is the prevention of exercise at the level of repair, and consequently the transfer of stress at the upper and lower levels. These additional loading stresses inevitably also result in these disc-level deformations.
[0008]
The patent publication discloses several devices for total disc replacement (i.e., artificial discs) whereby the damaged disc is removed and the device is secured to the vertebrae above and below the damaged disc. Has been disclosed. The ultimate goal of such a design concept is to maintain or reacquire the motility of the natural, vertebra-disc-vertebra motion segment. Various degrees of motility claim different types of mechanical disc replacement. The following is a non-exhaustive list of such US patent publications. USP 4,309,777 to Patil; USP 5,865,845 to Thalgot; USP 5,827,328 to Buttermann; USP 5,865,846 to Bryan et al. US 5,071,437 to Lee et al., USP 4,911,718; and US Pat. No. 4,714,469 to Kenna. The use of these conventional design proposals has been limited primarily by the inability to properly anchor flexible discs to the bony vertebrae.
[0009]
Another approach to repairing a damaged or diseased disc is to physically prevent disc collapse through insertion of a rigid body into the disc space. In addition, the insertion of a tubular or other hollow device, including an opening through its wall to allow bone to grow through the device, allows the motion segment to fuse with the maintained disc space. These orifices or tubular devices can be used in traditionally implantable medical devices from alloys (stainless steel, titanium and titanium alloys), carbon fiber reinforced engineering thermoplates (eg, polyetheretherketone), or mechanized human cortical bone. Can be built from These devices include, for example, USP 4,961,740 to Ray et al .; US Pat. No. 5,015,247 to Michelson; USP 5,766,253 to Brosnahan; USP 5,425,772 to Brantigan; , 814,084. Although these devices can maintain adequate spacing between vertebrae (i.e., disc height), they eliminate movement across the vertebra-disc-vertebral element when the two vertebrae fuse. Have disadvantages.
[Problems to be solved by the invention]
[0010]
Another common technique for preventing vertebral body separation is to replace the removed disc nucleus tissue with a non-fused, non-rigid material. One prior proposal suggests a sac that can be filled with fluid to restore disc height (USP 3,875,595 to Froning). Another prior proposal, disclosed in US Pat. No. 5,534,028 to Bao et al., Has a pre-cast pre-formed hydrogel placed in the void. Variations of this type of device of Bao et al. ('028) are also disclosed in USP 5,976,186, USP 5,192,326, USP 5,047,055. Inserts preformed from xerogel plastics as nucleus pulposus replacements are also disclosed in US Pat. No. 6,264,695. Cylindrical hydrogel pillows contained within non-expandable casings and related variants are described in USP 4,772,287, USP4,904,260, USP5,674,295, USP5,824,093, USP6,022,376. Has been described. In this regard, the device shown in US Pat. No. 6,022,376 is capable of being rehydrated and swelled once inserted as a dehydrated hydrogel resin into a tunnel carved inside the disc. The swelling supports the position of the device while preventing collapse of the nuclear emptying disc. However, the device is not fixed chemically or mechanically in place.
[0011]
It is disclosed in US Pat. Nos. 6,183,581, 6,206,921 and 6,264,659 that melted Gutta percha and its compounds can be used as potential replacements of the nucleus pulposus.
[0012]
[Means for Solving the Problems]
In general, the invention relates to an external biological tissue member that at least partially defines a void, and fills the void and inserts between the surrounding biological tissue members to chemically bond the tissue of the surrounding biological tissue member. The present invention relates to a bioartificial device made of a protein-like biopolymer to be bound (coupled). In a preferred aspect, the bioprosthetic device is a bioprosthetic disc having a fibrous outer annulus formed by defining and enclosing an internal cavity and removing at least a substantial portion of the natural glue-like core therefrom. The void defined from the fibrous outer ring can then be filled with a flowable biopolymer material and then at least partially solidified in situ (eg, most preferably by an in situ crosslinking reaction) It is possible to form a protein-like biopolymer in the void.
[0013]
The flowable biopolymer material is most preferably a liquid mixture of a protein material of human or animal origin and a di- or polyaldehyde. Thus, when introduced into the void, the liquid mixture can then react to form a crosslinked biopolymer in situ within the void, thereby forming a bioartificial device there. The liquid mixture can be formed previously introduced into the void or formed simultaneously during introduction into the void.
[0014]
These and other aspects and advantages will become more apparent upon careful consideration of the following description of preferred exemplary embodiments of the invention.
[0015]
BEST MODE FOR CARRYING OUT THE INVENTION
As used herein and in the claims, terms such as "bioprosthetic device" refer to the combination of a biological tissue member and a proteinaceous biopolymer that is chemically bonded (coupled) to the tissue of the tissue member. I do.
[0016]
The accompanying drawings show a segment of the patient's spine VC with the bioprosthetic disc 10 of the present invention interposed between adjacent ones of the individual vertebrae V. Bioprosthetic disc 10 essentially includes the fibrous outer annulus 10-1 of the patient's natural disc after removal of the glue core. The fibrous outer ring 10-1 thus binds and defines the interior cavity into which the proteinaceous biopolymer 10-2 is injected in situ. The protein-like biopolymer (hereinafter, usually more simply referred to as "biopolymer") 10-2 thus completely fills the disc space remaining after removal of the natural glue-like core of the patient's natural disc. Biopolymer 10-2 thus functions as a shock absorber, etc., similar to the natural function that can be attributed to the removed glue-like core.
[0017]
Virtually any suitable proteinaceous biopolymer can be used in the practice of the present invention. In this regard, terms such as "protein-like biopolymer" refer to polymerizable or copolymerizable materials that include one or more units in a polymer chain composed of natural, synthetic, or sequence-modified proteins or polypeptides, and the like. Mixtures and blends of various polymerizable and / or copolymerizable substances.
[0018]
One particularly preferred biopolymer 10-2 that can be used in the practice of the present invention is initially Part A: about 27-53% by weight of the mixture of water-soluble proteinaceous substances Part B: Proteins 20-69 present in the mixture Cross-linking reaction product of a two-part mixture consisting of a di- or polyaldehyde present in a weight ratio of 1 part by weight per part by weight and optionally comprising water and a composition comprising non-essential components. is there.
[0019]
Part A of the mixture is most preferably substantially an aqueous solution of a proteinaceous substance of human or animal origin. Albumin, including ovalbumin, is a preferred protein. Serum albumin of human or animal origin is particularly preferred. The proteinaceous substance can be a purified protein or a mixture based on proteins such as serum albumin. For example, a solid mixture obtained by dehydration of plasma or serum, or a commercially available solution of stabilized plasma protein, can be used to prepare Part A. These mixtures are known to contain albumin as a major component thereof, commonly referred to as plasma solid or serum solid, on the order of 50-90%. As used herein, the term "plasma" refers to whole blood from which blood cells have been removed by centrifugation. The term “serum” further refers to plasma that has been treated to prevent aggregation by inhibiting fibrinogen and / or fibrin removal or by inhibiting the clot formation of fibrin by the addition of a reagent such as citrate or EDTA. The proteinaceous substance can also include an effective amount of hemoglobin.
[0020]
Part B is essentially an aqueous solution of a di- or polyaldehyde. These materials are widespread and their utility is often limited by their availability and solubility in water. For example, aqueous glyoxal (etandial) is useful, and aqueous glutaraldehyde (pentanedial) is also useful. Also useful are aqueous mixtures of di- or polyaldehydes prepared by oxidative cleavage of appropriate carbohydrates with periodates, ozone, and the like. Glutaraldehyde is the preferred dialdehyde component of Part B. When combining parts A and B, the resulting product is a fast-setting, strong, flexible, leather-like or rubber-like substance, with a short mixing time, usually 15-30 seconds. become. Most preferred materials for use in the present invention are CryoLife, Inc. of Kennesaw, Georgia under the name "BIOGLUE". (See also US Pat. No. 5,385,606, the entire contents of which are incorporated herein by reference).
[0021]
The two components A and B above are pre-mixed and then applied and simultaneously mixed and delivered via an in-line mixing / dispenser tip during filling of the tissue-shaped void. Either. In the reaction of the two components, the resulting biological material is a hydrogel that adheres to the surrounding tissue and inserts into the voids of the surrounding tissue, is space-filled, mechanically and biologically stable for a period of time. The substance may be apparently solid or spongy. Additionally, organic or inorganic salts or other particulate matter may be included to modify the physical properties of the resulting bioartificial device. Preferably, biopolymer 10-2 will exhibit a compressive strength of at least 300 kPa (preferably about 300 to about 600 kPa), a compressive modulus of 2.5 MPa, a creep modulus of 1.0 MPa. The final compressive strength of biopolymer 10-2 can be adjusted by changing the composition of the protein and crosslinker components and / or by adding various fillers.
[0022]
As already mentioned, proteinaceous biopolymers that can be used in the practice of the present invention can be included as natural, synthetic or sequence-modified (ie, so-called "engineered") polypeptides on a reactive component. (Eg, US Pat. No. 6,018,030; US Pat. No. 5,374,431; US Pat. No. 5,606,019 or US Pat. No. 5,817,303, all of which are hereby incorporated by reference). Thus, although many of the examples below use albumin, those skilled in the art will appreciate that other reactable components can be used satisfactorily. Reactive synthetic polymerizable components, that is, those containing functional groups that cause crosslinking (eg, polyethylene-glycol polymers derivatized with electrophilic and nucleophilic groups such as amines, succinimidyls, anhydrides, and thiols) are also included. , Can be used in the practice of the present invention. In this regard, see US Pat. No. 6,166,130; US Pat. No. 6,051,648; or US Pat. No. 5,900,245, the entire contents of which are incorporated herein by reference.
[0023]
The slight compression mechanical properties obtained are similar to those of the disc and lumbar vertebra. The compressive properties of the described biological material 10-2 are very similar to the rigid materials traditionally used as implantable structural components such as stainless steel, titanium, polyacrylate bone cement, ceramics or carbon fiber composites. Differently, this results in better biomaterial compatibility with the selected instructions. For example, the bioprosthetic discs of the present invention exhibit flexibility comparable to the natural discs of living organisms. More specifically, the bioprosthetic disc exhibits flexibility comparable to a biological natural disc after at least about 5 million cycles of a load of about 0.85 Mpa.
[0024]
The particular properties of biopolymer 10-2 can be engineered to suit the use of a particular end. For example, a biopolymer can include a fibrous or particulate reinforcement ("filler") material as long as it is biocompatible.
[0025]
Thus, natural or synthetic fibers, such as virtually any desired denier polyester, nylon, polyolefin, glass, etc., can be used in the form of continuous lengths of single fibers (ie, monofilaments) or in the form of twisted yarns. It can be used in the form of a roving or a multifilament rope. Further, the reinforcing medium may be in the form of staple fibers of a predetermined length spun into a twisted yarn, rovings and / or ropes of the desired denier and continuous length. The mono- or multi-filament reinforcing material may be in the form of a woven or non-woven structure. It is sufficient here to say that fibrous reinforcing materials in virtually any physical form can be used satisfactorily in the practice of the invention.
[0026]
The reinforcing material can also be in the form of particles, such as synthetic or natural organic and inorganic particulate reinforcing materials. Some representative examples of such particles include calcium carbonate, calcium phosphate, hydroxyapatite bone chips, ceramic particles, and the like.
[0027]
The present invention is further described by reference to the following non-limiting examples.
[0028]
【Example】
[Example 1]
The formulation composed of the protein solution (serum albumin) and the crosslinker (glutaraldehyde) was placed in another chamber of the delivery device. When the apparatus is started, the two components are discharged from their respective chambers and placed in a mixing chip, where the two solutions are blended, mixed and conveyed to a stationary mixing element present in the chip. A medical needle is attached to the mixing tip and the formulation is injected into the space distal to the vertebrae of the explant pig spine. The tip can be mounted, for example, on a needle, catheter, or other hollow tubular device for delivery. After 30 seconds, the needle was withdrawn from the injection site. The injected material then polymerized and did not ooze out of the needle hole. After 2 minutes, the disc-vertebral plate was cut and the presence of biological material was seen.
[0029]
Example 2: Calf spine was obtained from a commercial slaughterhouse and the vertebral body and discs were exposed by blunt dissection and sharp dissection. A 4 mm hole was drilled in the anterior surface of the disc so that the drill bit was inserted into the center of the nucleus. Nuclear material was removed using surgical forceps and a curette. The hollow space was filled with the formulation described in Example 1. The injected material then polymerized and did not ooze out of the needle hole. After 2 minutes, the disc-vertebral plate was cut and the presence of biological material was seen.
[0030]
Example 3 A calf spine was obtained from a commercial slaughterhouse and the vertebral body and intervertebral disc were exposed by blunt dissection and sharp dissection. The upper and lower m vertebrae were cut parallel to each other at mid-height using a ruler for the vestibule to obtain a bone / disc / bone motion segment. A 4 mm hole was drilled in the anterior surface of the disc so that the drill bit was inserted into the center of the nucleus. Nuclear material was removed using surgical forceps and a curette. The hollow space was filled with the formulation described in Example 1. The injected material then polymerized and did not ooze out of the needle hole.
[0031]
Once polymerization had occurred, the construct could be manually compressed in the anterior-posterior axis and in the left-right axis, indicating that flexibility was retained after repair of this segment. The composition was then placed in a biological material testing device (Instron electromechanical test station) and compressed repeatedly at a load of 700 N to condition the composition. Thereafter, a steady load of 700 N was applied, and compression creep was measured. The load was held for 10 minutes. During this time, the polymerized material did not ooze out of the distal space or hole. The force of 700 N is the value listed in the publication as the load experienced by the lumbar disc when an average structured human stands. The experiment was repeated on five separate samples.
[0032]
In this example, the motion segment height was measured before nucleus removal, after nucleus removal, after filling with biological material, and after unloading. It has been found that (1) removal of the nucleus reduces the overall height and compressibility of the material, and (2) overlaying with biological material restores disc height and compressibility. Was.
[0033]
[Example 4]: By injecting the volume of the substance described in Example 1 into the void volume of the substance, the intervertebral disc of the formed biological substance is subjected to a minimum stress of 200 kPa and a maximum stress of either 470 or 800 kPa. Compressed between 100 and 1000 cycles at a compression rate of 100 mm / min (normal lumbar intervertebral disc, cross-sectional area 1500 mm ² , corresponding to a load of 300 N and 700 or 1200 N). The disc element did not show any breakage, permanent deformation, or loss of hydration (weight loss analysis). The 1200 N force is the value described in the publication as the compressive load experienced by the lumbar spinal disc when a person of average structure bends forward.
[0034]
Example 5: Calf spine was obtained and prepared as described in Example 3. In this example, the nucleus pulposus was accessed from either the anterior or posterior aspect. The constructs were then placed in a cyclic load of 0.85 MPa at 5 Hz and the load was applied for more than 5 million cycles. During this time, the composition was kept in saline containing a non-fixing fungicide. At the end of the test period, the construct was removed, the disc was sliced parallel to the end plate, and the condition of the implant was observed. The implants present in the voids formed by removal of the nucleus pulposus were flexible as such.
[0035]
Example 6: A sample of biological material was formed as described in Example 4. The biological material was then placed at a cycle load of 0.5 MPa at about 2 Hz and the load was applied for more than 5 million cycles or for more than 10 million cycles. During this time, the construct was kept in saline containing a non-fixing fungicide. The test sample remained intact for the duration of the test, with a height loss of less than 10% of the initial height.
[0036]
Although the present invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, the present invention is not limited to the disclosed embodiment, but is within the spirit and scope of the appended claims. It is to be understood that the present invention is intended to cover various modifications and equivalent arrangements included in the above.
[Brief description of the drawings]
FIG. 1 is a schematic view of a portion of a patient's spine showing an intervertebral disc bioprosthesis of the present invention interposed between adjacent vertebrae.
[Explanation of symbols]
10 Bioartificial device 10-1 External biological tissue member 10-2 Protein-like biopolymer

Claims (42)

An external biological tissue member that at least partially defines the void, and a polymerizable material that fills the void, is inserted between the surrounding biological tissue members, and chemically bonds to the tissue of the surrounding biological tissue member. combination. The combination according to claim 1, wherein the polymerizable substance is a protein-like biopolymer. The combination of claim 1 wherein the polymerizable material comprises a fibrous or particulate filler material. 3. The combination according to claim 2, wherein the biopolymer is a cross-linking reaction product of a protein material of human or animal origin with a di- or polyaldehyde. 5. The combination of claim 4, wherein said protein is bovine or human serum albumin or hemoglobin. The combination of claim 5, wherein said aldehyde is glutaraldehyde. 7. The combination according to any one of claims 1 to 6, wherein the combination is in the form of an intervertebral disc. The combination of claim 7, wherein the disc remains flexible after 5 million cycles of a 0.85 MPa cycle load. 3. The combination of claim 2, wherein the proteinaceous biopolymer is a reaction product of at least two reactable components, one of the components comprising a natural, synthetic or sequence-modified polypeptide. The combination of claim 1, wherein the polymerizable material is a reaction product of at least two reactable components, one of the components comprising a synthetic polymerizable component comprising a crosslinkable functional group. The combination of claim 10, wherein the synthetic polymerizable component comprises a polyethylene glycol polymer derivatized with an electrophilic and / or nucleophilic group. The combination according to claim 11, wherein the electrophilic and / or nucleophilic group comprises at least one selected from amine, succinimidyl, anhydride, and thiol groups. A fibrous outer ring that remains after removal of the glue-like core from the natural biological disc, thereby defining an internal void, and a protein-like material that fills the void and is inserted between biological tissues surrounding the fibrous outer ring. A bioartificial disc made of biopolymer. 14. The bioprosthetic disc of claim 13, which exhibits flexibility comparable to a natural disc of an organism. 15. The bioprosthetic disc according to claim 14, which exhibits a flexibility comparable to a natural disc of an organism after 5 million cycles of a cyclic load of 0.85 MPa. 15. The bioprosthetic disc of claim 14, wherein the biopolymer comprises a fibrous or particulate filler material. 14. The bioprosthetic intervertebral disc according to claim 13, wherein the biopolymer is a cross-linking reaction product of a human or animal-derived protein substance with a di- or polyaldehyde. The bioartificial disc according to claim 17, wherein the protein is bovine or human serum albumin or hemoglobin. 19. The bioartificial disc according to claim 17 or 18, wherein the aldehyde is glutaraldehyde. A bioprosthesis, comprising filling an at least partially void defined by surrounding biological tissue material with a flowable polymerizable material in situ within the void, thereby forming a bioprosthesis. In-situ formation method. 21. The method of claim 20, comprising injecting a flowable proteinaceous biopolymer into the void and at least partially solidifying the proteinaceous biopolymer in situ therein. 21. The method of claim 20, wherein the method comprises injecting at least two reactive biopolymer components in situ within the void and allowing the reactive biopolymer components to at least partially solidify by a crosslinking reaction therebetween. Method. 22. The method of claim 21, wherein the at least two reactive components are premixed before being injected into the void. 22. The method of claim 21, wherein the at least two reactable components are mixed simultaneously with the injection into the void. Said at least two reactable components comprise a liquid mixture composed of a protein material of human or animal origin and a di- or polyaldehyde, wherein said liquid mixture is in situ crosslinked protein-like biomass inside the cavity. 22. The method of claim 21, wherein the method forms a polymeric material. 26. The method of claim 25, wherein the protein material and the di- or polyaldehyde are pre-mixed before being introduced into the void. 26. The method of claim 25, wherein the proteinaceous material and the di- or polyaldehyde are mixed at the same time as they are introduced into the void. 26. The method of claim 25, comprising providing a fibrous or particulate filler material in the liquid mixture. 22. The method of claim 21, wherein the proteinaceous biopolymer is a reaction product of at least two reactable components, one of the components comprising a natural, synthetic or sequence-modified polypeptide. 21. The method of claim 20, wherein the polymerizable material is a reaction product of at least two reactable components, one of the components comprising a synthetic polymerizable component that includes a crosslinkable functional group. 31. The method of claim 30, wherein the at least one reactive component comprises a polyethylene glycol polymer derivatized with an electrophilic and / or nucleophilic group. 32. The method of claim 31, wherein the electrophilic and / or nucleophilic group comprises at least one selected from an amine, succinimidyl, anhydride, and a thiol group. (A) Providing an intervertebral disc having a fibrous outer ring, the fibrous outer ring formed by removing at least a substantial portion of the glue-like core therefrom, surrounding and defining an internal cavity. Yes;
(B) filling the void defined by the fibrous outer ring with a flowable polymeric material; and (c) at least partially solidifying the polymeric material in situ within the void. , A method for forming a biological artificial disc. The method according to claim 33, wherein the polymerizable substance is a protein-like biopolymer. 34. The method of claim 33, wherein the method comprises injecting at least two reactive biopolymer components in situ within the void and allowing the reactive biopolymer components to at least partially solidify by a reaction therebetween. . 36. The method of claim 35, wherein the at least two reactive components are premixed before being injected into the void. 36. The method of claim 35, wherein the at least two reactable components are mixed while being injected into the void. The at least two reactable components comprise a liquid mixture of a protein material of human or animal origin and a di- or polyaldehyde, wherein the liquid mixture has an in situ cross-linked proteinaceous biopolymer material within the void space 36. The method of claim 35, wherein is formed. 39. The method of claim 38, wherein the protein material and the di- or polyaldehyde are pre-mixed before being introduced into the void. 39. The method of claim 38, wherein the protein material and the di- or polyaldehyde are mixed at the same time as they are introduced into the void. 39. The method of claim 38, comprising providing a fibrous or particulate filler material in the liquid mixture. 34. The method of claim 33, wherein step (a) is preceded by step (a1) of removing a substantial portion of the glue-like core of the disc to leave a fibrous outer annulus defining an internal void.